Identifying patients at risk for life threatening arrhythmias

ABSTRACT

The invention is a method for identifying proteins associated with sudden cardiac death (SCD) and for assessing a patient&#39;s risk of SCD by determining the amount of one or more SCD-associated proteins in the patient. Typically, the patient submits a sample, such as a blood sample, which is tested for one or more SCD-associated proteins. Based upon the results of the tests, the patient&#39;s risk of SCD may be assessed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.11/157,549, filed on Jun. 21, 2005, which is a continuation-in-part fromU.S. application Ser. No. 11/050,611, filed on Feb. 3, 2005, whichclaims priority from U.S. Provisional Application No. 60/541,004, filedon Feb. 5, 2004.

This application is related to the application entitled “Self-ImprovingClassification System” and “Self-Improving Identification Method,” whichwere filed on Jun. 12, 2005 and also assigned to Medtronic, Inc.

BACKGROUND OF THE INVENTION

The present invention relates to a system and method for identifyingcandidates for receiving cardiac therapy based on biochemical markersassociated with propensity for arrhythmias.

Many patients experiencing ventricular tachyarrhythmia may be at risk ofloss of heart function. Sudden cardiac death, which results from a lossof heart function, is often preceded by episodes of ventriculartachyarrhythmia such as ventricular fibrillation (VF) or ventriculartachycardia (VT). Many patients are unaware that they are at risk ofventricular tachyarrhythmia. For some unfortunate patients, a suddencardiac death incident may be the first sign that they were at risk. Itis, of course, preferable for such patients to be aware of their risk inadvance of such an event. In patients who are aware of their risk, animplantable medical device, such as a pacemaker with defibrillation andcardioverson capability, may drastically increase the survival rates ofsuch patients.

BRIEF SUMMARY OF THE INVENTION

In general, the invention is directed to systems and techniques forassessing a risk of ventricular tachyarrhythmia in a patient. In somemedical conditions, including but not limited to ventriculartachyarrhythmia, certain biochemical factors in the body of the patientreflect the health of a patient. A patient that experiences ventriculartachyarrhythmia, for example, may experience an increased or decreasedconcentration of identifiable proteins in his/her blood, even if thepatient is symptom free. By measuring the concentration of thesebiochemical markers or “biomarkers” in the patient, an assessment of arisk of ventricular tachyarrhythmia for the patient can be made, basedupon the measurements.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a conceptual logical diagram illustrating an embodiment of theinvention.

FIG. 2 is a conceptual logical diagram illustrating a variation of theembodiment of the invention shown in FIG. 1.

FIGS. 3 and 4 are flow diagrams illustrating techniques for assessmentof risk of ventricular tachyarrhythmia.

FIG. 5 is a conceptual diagram illustrating a technique for massspectral analysis of a sample for biochemical markers.

FIG. 6 is a graph showing differences in biochemical marker abundancefor a patient at risk of ventricular tachyarrhythmia, compared to apatient in a control group.

FIG. 7 is a logical diagram illustrating a technique for sortingpatients at risk of ventricular tachyarrhythmia from a control group.

FIG. 8 is a logical diagram illustrating a technique for classifyingpatients at risk of ventricular tachyarrhythmia.

FIG. 9 is a block diagram of a system configured to carry out anembodiment of the invention.

DETAILED DESCRIPTION OF THE INVENTION

FIG. 1 is a conceptual logical diagram illustrating an embodiment of theinvention. Based upon measuring one or more biochemical markers in agroup of patients 10, the invention provides for assessing a risk ofventricular tachyarrhythmia in each patient as a function of themeasurement.

In the illustration shown in FIG. 1, a “tree analysis” sorts thepatients into groups according to measurements of three biochemicalmarkers. The biochemical markers are identified by the letters “A,” “B,”“C” and “D.” Typical biochemical markers include proteins (thatincludes, for example, peptides, polypeptides, and polyamino acids ofany length or conformation), lipids, genes and peptides or anycombination thereof, but the illustration shown in FIG. 1 is not limitedto any particular biochemical marker or set of biochemical markers.Specific examples of biochemical markers are discussed below.

For each patient, a measure of a first biochemical marker (denoted MA)is determined. Determining the measure of biochemical marker “A” for aparticular patient may include, for example, determining theconcentration or mass of biochemical marker “A” in a standard sample ofbodily fluid taken from that patient. For each patient, the measure ofthe first biochemical marker is compared to a threshold value (denotedT_(A)). Those patients for whom MA is greater than or equal to T_(A) aredeemed to be in a group 12 that is not at significant risk ofventricular tachyarrhythmia, and no further testing need be done for themembers of group 12. Those patients for whom M_(A) is less than T_(A)are deemed to be in a group 14 that may be, or may not be, at risk ofventricular tachyarrhythmia. In FIG. 1, the members of group 14 undergofurther testing to determine the individual members' risks ofventricular tachyarrhythmia.

For each patient in group 14, a measure of a second biochemical marker“B” (denoted M_(B)) is determined. For each patient in group 14, themeasure of the second biochemical marker is compared to a secondthreshold value (denoted T_(B)). Those patients for whom M_(B) is lessthan T_(B) are deemed to be a group 16 that is not at significant riskof ventricular tachyarrhythmia, and no further testing need be done forthe members of group 16. Those patients for whom M_(B) is greater thanor equal to T_(B) are deemed to be in a group 18 that may be, or may notbe, at risk of ventricular tachyarrhythmia.

The members of group 18 undergo further testing with respect to ameasure of a third biochemical marker “C” (denoted M_(C)). For eachpatient in group 18, the measure of the third biochemical marker iscompared to a third threshold value (denoted T_(C)). On the basis of thecomparison, the patients are divided into a group 20 that is not atsignificant risk of ventricular tachyarrhythmia and a group 22 that isat significant risk of ventricular tachyarrhythmia.

In other words, FIG. 1 illustrates assessing a risk of ventriculartachyarrhythmia for a patient as a function of the measurement of threebiochemical markers. Unless a patient meets the threshold criteria forall three biochemical markers, the patient will not be deemed to be atsignificant risk of ventricular tachyarrhythmia.

The thresholds T_(A), T_(B) and T_(C) are determined empirically.Clinical studies and experience may be used to determine thresholds foreach biochemical marker. The thresholds may differ from marker tomarker. For some biochemical markers, a patient may be at higher riskwhen the measure of the biochemical marker is above the threshold, andfor other biochemical markers, the patient may be at higher risk whenthe measure of the biochemical marker is below the threshold.

FIG. 2 is a conceptual logical diagram illustrating an embodiment of theinvention that is a variation of the technique illustrated in FIG. 1.Unlike FIG. 1, patients sorted into group 12 are subjected to furthertesting. For each patient in group 12, a measure of a fourth biochemicalmarker “D” (denoted MD) is determined, and the measure is compared to afourth threshold value (denoted T_(D)). On the basis of this comparison,patients in group 12 are sorted into groups 24 and 26. Those patients ingroup 24 are deemed to be not at significant risk of ventriculartachyarrhythmia, and no further testing need be done for the members ofgroup 24.

Those patients in group 26, however, are subjected to further testing.The members of group 26 undergo further testing with respect to thethird biochemical marker “C,” just like the members of group 18. On thebasis of a comparison of the measure of the third biochemical marker tothe third threshold, the patients in group 26 are divided into a group28 that is not at significant risk of ventricular tachyarrhythmia and agroup 30 that is at significant risk of ventricular tachyarrhythmia.

In other words, FIG. 2 illustrates assessing a risk of ventriculartachyarrhythmia for a patient as a function of the measurement of fourbiochemical markers. A patient may be deemed to be at significant riskof ventricular tachyarrhythmia according to more than one testing path.

FIG. 3 is a flow diagram illustrating logical sorting embodiments suchas are depicted in FIGS. 1 and 2. An apparatus, such as an apparatuslisted in FIGS. 5 and 6, or a technician measures a first biologicalmarker (40) and assesses a risk of ventricular tachyarrhythmia in thepatient as a function of the measurement (42). The apparatus ortechnician measures a second biological marker (44) and assesses therisk of ventricular tachyarrhythmia in the patient as a function of thatmeasurement (46).

In the procedure outlined in FIG. 4, the apparatus or technicianmeasures a first biological marker (50) and measures a second biologicalmarker (52), and assesses the risk of ventricular tachyarrhythmia in thepatient as a function of both measurements (54). The techniques shown inFIGS. 3 and 4 may achieve the same result; that is, a patient may besorted according to risk of ventricular tachyarrhythmia using eithertechnique. When a patient is deemed to be at risk, an appropriatetherapy may be applied. Therapy for a patient may include, for example,implanting an electronic cardiac stimulation device in the patient thatdetects and terminates episodes of ventricular tachyarrhythmia oradministering an antiarrhythmic drug that prevents induction of suchepisodes.

FIG. 5 is a conceptual diagram illustrating a technique for measuring aplurality of biological markers. A biochip 60 comprises a substrate 62and one or more elements 64A. In FIG. 5, four distinct sensing elementsare coupled to substrate 62, but the invention encompasses use of anynumber of sensing elements.

Biochip 60 is a set of miniaturized test sites, or microarrays, arrangedon a solid substrate 62 made from a material such as silicone or glass.Each test site includes a set of sensing elements 64A. In general,sensing elements include one or more components that change conformationin the presence of an analyte of interest. Typical sensing elementsinclude antibody molecules that change conformation in the presence of aspecific biomarker but that do not change conformation in the presenceof any other biomarker. The invention encompasses any sensing element,however, and is not restricted to antibodies. The sensing elements ofbiochip 60 may have general properties such as high affinity towardhydrophilic or hydrophobic molecules, or anionic or cationic proteins,for example.

Substrate 62 may have a surface area of about one square centimeter, butthe invention encompasses biochips that are larger or smaller. Substrate62 may be formed in any shape, may include any number of test sites, andmay include any combination of sensing elements. The invention is notlimited to any particular biochip.

Biochip 60 is exposed to sample 66. Sample 66 may include any biologicalsample from a patient, such as a blood sample. Biomarkers present insample 66 react with sensing elements on biochip 60. Exposed sensingelements 64B typically react with biomarkers in sample 66 by undergoinga conformational change, or by forming ionic, covalent or hydrogenbonds. The unreacted or unbound portion of sample 68 is washed away.

The concentrations of biomarkers in sample 66 are a function of theextent of the reaction between exposed sensing elements 64 and sample66. The extent of the reaction is determinable by, for example, massspectrometry. The Surface Enhanced Laser Desorption/Ionization (SELDI)process is an example of a mass spectrometry technique for determiningthe concentrations of biomarkers that does not necessarily needantibodies. Instead, the molecules are absorbed onto a surface, andlater released from the same surface with its energy absorbing matrixupon the application of external energy, usually in the form of light.

In general, the SELDI process directs light generated by one or morelight sources 70 at biochip 60. A mass analyzer 72 measures themolecular weight of the biomarkers. In particular, biomarkers on biochip60 are ionized and separated, and molecular ions are measured accordingto their mass-to-charge ratio (m/z). Ions are generated in theionization source by inducing either the loss or the gain of a charge(e.g. electron ejection, protonation, or deprotonation). Once the ionsare formed in the gas phase, they can be electrostatically directed intomass analyzer 72, separated according to their mass, and finallydetected.

Proteins bound to sensing elements 64B, for example, can be ionized andseparated based on molecular properties, such as being hydrophilicversus hydrophobic. Proteins captured by sensing elements 64B are freedby the energy provided by a weak laser pulse, and charged positively bythe removal of a second electron as a result of illumination by a secondlaser pulse. Time of flight though a vacuum tube following accelerationin an electric field allows the measurement of the mass-to-charge ratio.

The invention supports other techniques for determining theconcentrations of biomarkers and is not limited to the SELDI process. Inone embodiment, for example, the techniques of the invention could becarried out by using conventional assays for individual biomarkers, suchas an Enzyme Linked ImmunoSorbent Assay (ELISA tests). An advantage ofusing a biochip is that a biochip saves time and effort in comparison toindividual assays when multiple markers are to be measured.

Many protein markers are generally accepted as being indicative ofcardiac conditions. C-Reactive Protein (CRP) is associated with suddencardiac death; Fatty Acid Binding Protein is a plasma marker associatedwith acute myocardial infarction; Cardiac Troponin is associated withmyocardial infarction; Myosin Light and Heavy Chains are associated withheart failure; brain natriuretic peptide (BNP) is associated with leftventricular heart failure, and so on.

Other markers may be associated with other cardiac conditions ofinterest. The markers may be identified by their name, or by othercharacteristics, such as molecular weight.

In an example clinical study, patients with coronary artery disease weredivided into two groups: a test group that had coronary artery disease,and an implantable medical device (IMD) (with one sustained VT/VFepisode with cycle length less than or equal to 400 ms); and a controlgroup having coronary artery disease but no IMD, and no known history ofVT/VF. In the study, sixteen patients had an IMD and thirty-two were inthe control group. Certain patients were excluded from the study,including non-Caucasians, females, patients outside of an age limit of45-80, and patients having certain health problems or cardiacconditions. Patients meeting the inclusion criteria were enrolled in thestudy. Upon enrollment, an extensive questionnaire, including medicalhistory, was filled.

Three blood samples were drawn from each patient. At least one samplecomprised 8.5 mL of blood drawn from the patients for serum separation.Serum is the cell free portion of the blood containing proteins andlipids. At least one other sample of an additional 12 mL of blood wasdrawn and kept as whole blood for eventual genetic analysis. The sampleswere analyzed using proteomic and lipidomic techniques.

During processing, proteins in the serum were fractionated into fourdistinct groups based on pH (acidity) of the protein. Later on, theseproteins were spotted onto three surfaces of one or more biochips. Thesurfaces had different chemical affinities. A surface designated “CM10”was responsive to weak cation exchange surface. A surface designated“H50” was a hydrophobic surface. A surface designated “IMAC” was animmobilized metal affinity surface. The SELDI time-of-flight techniquewas used to measure the molecular weight of the protein on each surface.

FIG. 6 shows the results of sample proteomic spectra of two patients,one having an IMD (80) and one in the control (82). These resultsindicate that some of the protein markers in the blood were expresseddifferently in two groups. Data produced by processing of all of thepatients followed similar patterns, i.e., the data indicated that someof the protein markers in the blood obtained from patients wereexpressed differently in two groups. The differences in markers may forma basis for distinguishing the patients that would benefit from an IMDfrom the patients that would not benefit.

FIG. 7 shows a tree analysis applied to these results to identifypotential biomarkers that differentiate patients who have a higherpropensity for fatal ventricular arrhythmias from the others. As aresult of the tree analysis, four protein markers could be used toclassify the 48 patients correctly. Specifics of these protein markersare shown in the table below:

Protein Molecular Isoelectric pH Number Weight (Da) (pl) Capture SurfaceP1 10,146.5 9+ CM10 weak cation exchange) P2 15,006 9+ CM10 weak cationexchange) P3 166,582 5-7 CM10 weak cation exchange) P4 10,948 9+ IMAC(Immobilized Ion Affinity Surface)

In the above table, proteins are identified by a number and arecharacterized by a molecular weight in Daltons and an Isoelectric pH(pI). The molecular weight in Daltons is not necessarily unique to anyparticular protein, but proteins are often distinguishable by molecularweight. It is not necessary to the invention that the protein havingthat molecular weight and/or pI be specifically identified by name or byamino-acid sequence.

As shown in FIG. 7, the amount of protein P1 in the serum was tested forall patients 90. Patients 92 having an abundance of P1 greater than orequal to 1.0422237 (measured in arbitrary units) were not at significantrisk of ventricular tachyarrhythmia and were, therefore, not candidatesfor an IMD. Patients 94 having an abundance of P1 less than 1.0422237,however, could not be classified by abundance of P1 alone.

For patients 94, the amount of P2 in the serum was tested. Patients 96having an abundance of P2 less than 0.2306074 were not candidates for anIMD. Patients 98 having an abundance of P2 greater than or equal to0.2306074 were tested for protein P3. Patients 100 having an abundanceof P3 greater than or equal to 0.0491938 were not candidates for an IMD,while patients 102 having an abundance of P3 less than 0.0491938 weretested for protein P4. Patients 104 having an abundance of P4 greaterthan 0.027011 were considered to be candidates for an IMD, while theremaining patients 106 were not considered to be candidates for an IMD.

The arbitrary units may be normalized to an abundant protein, such asalbumin, which is generally consistent in relative abundance among agroup of patients or by spiking the original sample with a knownconcentration of an exogenous substance, and scaling the entire spectrumsuch that the measured value of the exogenous compound matches theamount that was added to the sample. The invention supports the use ofother bench marks as well, such as the total ion current in the massspectrometer used to measure the protein abundance.

In addition, the invention supports a range of measurement standards. Insome cases, it is not feasible to perform measurements that have onehundred percent sensitivity and specificity, and some standards may beapplied to determine whether the patient is at significant risk ofventricular tachyarrhythmia or not. The tree analysis depicted in FIG.7, for example, is generally more sensitive and specific thanconventional patient sorting techniques (such as averagedelectrocardiogram), even though it may result in some false positivesand false negatives.

The tree shown in FIG. 7 may be generated using Classification andRegress Tree (CART) analysis. The tree analysis depicted in FIG. 7 is anexample of an approach for assessing a risk of ventriculartachyarrhythmia in one or more patients as a function of the measurementof one or more biochemical markers. The assessment may be preformed inother ways as well. The test may be expressed as a logical test such asan IF-THEN test, which can be implemented in software:

IF   ((P1>1.0422237) AND (P2≧0.2306074) AND (P3<0.0491928)   AND(P4≧0.027011)) THEN   PATIENT IS AN IMD CANDIDATE

This IF-THEN test gave the following results when applied to theclinical data where two samples from each patient were processed:

VT/VF NORMAL TEST (+) 27 1 TEST (−) 5 63

Sensitivity: 27/(27+5)=84%

Specificity: 63/(63+1)=98%

False Positives: 1/(1+27)=4%

False Negatives: 5/(5+63)=7%

Using conventional sorting techniques, sensitivity and specificity tendto be around 55 to 75 percent. This clinical data demonstrates animprovement in sensitivity and specificity in comparison to conventionaltechniques.

Another technique for assessing a risk of ventricular tachyarrhythmia inone or more patients as a function of a measurement of one or morebiochemical markers is to use an artificial neural network. In anexemplary application, the clinical data was analyzed using anartificial neural network having four input nodes corresponding toproteins P1, P2, P3 and P4. The network included four hidden nodes andone output. This artificial neural network gave the following resultswhen applied to the clinical data where two samples from each patientwere processed:

VT/VF NORMAL TEST (+) 24 1 TEST (−) 8 63

Sensitivity: 24/(24+8)=75%

Specificity: 63/(63+1)=98%

False Positives: 1/(1+25)=4%

False Negatives: 8/(8+63)=11%

A second representative clinical study to discover class identifiers wascarried out with an additional 30 patients. These additional patientsalso had coronary artery disease and met specific inclusion criteria.They were divided into the two groups based on whether or not patientshad an IMD. The patients having an IMD also had at least one true VT/VFepisode with a cycle length less than or equal to 400 ms terminated inthe last 90 days. A total of 29 patients were in the test group, whichconsists of patients with an IMD, and 49 patients were in the controlgroup.

Patients filled out an extensive questionnaire that included medicalinformation that was then used in creating specimen/patient profiles.The following table shows the patient characteristics included thespecimen profile and the relative breakdown between the test and controlgroups.

Patients in ICD Patients in Total Arm Control Arm Patients PatientCharacteristics (N = 29) (N = 49) (N = 78) Gender (N, %) Male 29 (100%) 49 (100%)  78 (100%) Female 0 (0%)  0 (0%) 0 (0%) Age (years) Mean68.8  67.1  67.8  Standard Deviation 8.2 8.1 8.1 Minimum-Maximum 50-8151-81 50-81 Left Ventricular Ejection Fraction Time since most recentLVEF (days) Mean 1.1 0.9 1   Standard Deviation 1.1 1.1 1.1Minimum-Maximum   0-5.3   0-4.8  0-53 Most Recent Documented Measurement(%) Mean 37.9  51.2  46.2  Standard Deviation 9.6 9.5 11.5 Minimum-Maximum 28-66 29-73 28-73 Method of LVEF MeasurementRadionucleotide 6 (21%) 19 (39%) 25 (32%) angiocardiography/MUGA Echo 9(31%) 16 (33%) 25 (32%) Cath 13 (45%)  14 (29%) 27 (35%) Unknown 0 (0%) 0 (0%) 0 (0%)

The next table shows patient cardiovascular surgical and medical historythat was included in the specimen profiles and the relative breakdownbetween the control and test groups.

Patients in Patients in Total ICD Arm Control Arm Patients PatientCharacteristics (N = 29) (N = 49) (N = 78) Cardiovascular SurgicalHistory (N, %) None 6 (20.7%) 4 (8.2%) 10 (12.8%) Coronary Artery BypassGraft 14 (48.3%) 20 (40.8%) 34 (43.6%) Coronary Artery Intervention 13(44.8%) 36 (73.5%) 49 (62.8%) Angioplasty 8 (27.6%) 25 (51%) 33 (42.3%)Stent 7 (24.1%) 31 (63.3%) 38 (48.7%) Atherectomy 0 (0%) 0 (0%) 0 (0%)Ablation 3 (10.3%) 3 (6.1%) 6 (7.7%) Valvular Surgery 1 (3.4%) 1 (2%) 2(2.6%) Other 1 (3.4%) 2 (4.1%) 3 (3.8%) Cardiovascular Medical HistoryNone 0 (0%) 0 (0%) 0 (0%) Coronary Artery Disease 29 (100%) 49 (100%) 78(100%) Myocardial Infarction 29 (100%) 49 (100%) (78 (100%) Number ofinfarctions Mean 1.4 1.3 1.3 Standard Deviation 0.6 0.5 0.5Minimum-Maximum 1-3  1-3  1-3  Time Since First Infarction (years) Mean10.2  6.6 7.9 Standard Deviation 7.7 5.6 6.6 Minimum-Maximum 1-26 0-220-26 Time Since Most Recent Infarction (years) Mean 5.3 5   5.1 StandardDeviation 5   5.4 5.2 Minimum-Maximum 1-17 0-22 0-22 Hypertension 19(65.5%) 34 (69.4%) 53 (67.9%) Cardiomyopathy 18 (62.1%) 3 (6.1%) 21(26.9%) Hypertrophic 5 (17.2%) 0 (0%) 5 (6.4%) Dilated 9 (31%) 3 (6.1%)12 (15.4%) Valve Disease/Disorder 4 (13.8%) 8 (16.3%) 12 (15.4%) Aortic0 (0%) 5 (10.2%) 5 (6.4%) Tricuspid 1 (3.4%) 1 (2%) 2 92.6%) Mitral 4(13.8%) 3 (6.1%) 7 (9%) Pulmonary 0 (0%) 0 (0%) 0 (0%)Primary/Idiopathic Electrical 0 (0%) 1 (2%) 1 (1.3%) Conduction DiseaseDocumented Accessory 0 (0%) 0 (0%) 0 (0%) Pathway ChronotropicIncompetence 1 (3.4%) 0 (0%) 1 (1.3%) NYHA Classification Class I 4(13.8%) 3 (6.1%) 7 (9%) Class II 6 (20.7%) 5 (10.2%) 11 (14.1%) ClassIII 4 (13.8%) 0 (0%) 4 (5.1%) Class IV 0 (0%) 0 (0%) 0 (0%) NotClassified 15 (51.7%) 41 (83.7%) 56 (71.8%) Congenital Heart Disease 0(0%) 0 (0%) 0 (0%) Other 2 (6.9%) 3 (6.1%) 5 (6.4%)

The table that follows shows patient arrhythmia history that wasincluded in the specimen profiles and the relative breakdown between thecontrol and test groups.

Patients in Patients in Total ICD Arm Control Arm Patients PatientCharacteristics (N = 29) (N = 49) (N = 78) Spontaneous ArrhythmiaHistory (N, %) None 0 (0%) 26 (53.1%) 26 (33.3%) Ventricular SustainedMonomorphic 23 (79.3%) 0 (0%) 23 (29.5%) VT Sustained Polymorphic VT 1(3.4%) 0 (0%) 1 (1.3%) Nonsustained VT 17 (58.6%) 0 (0%) 17 (21.8%)Ventricular Flutter 1 (3.4%) 0 (0%) 1 (1.3%) Ventricular Fibrillation 9(31%) 0 (0%) 9 (11.5%) Torsades de Pointes 0 (0%) 0 (0%) 0 (0%) Long Q/TSyndrome 0 (0%) 0 (0%) 0 (0%) Other 0 (0%) 2 (4.1%) 2 (2.6%)Bradyarrhythmias/ Conduction Disturbances Sinus Bradycardia 5 (17.2%) 14(28.6%) 19 (24.4%) Sick Sinus Syndrome 0 (0%) 2 (4.1%) 2 (2.6%) 1° AVBlock 7 (24.1%) 6 (12.2%) 13 (16.7%) 2° AV Block 0 (0%) 0 (0%) 0 (0%)Type I (Mobitz) 0 (0%) 0 (0%) 0 (0%) Type II (Wenckebach) 0 (0%) 0 (0%)0 (0%) 3° AV Block 0 (0%) 0 (0%) 0 (0%) Right Bundle Branch Block 5(17.2%) 8 (16.3%) 13 (16.7%) Left Bundle Branch Block 4 (13.8%) 2 (4.1%)6 (7.7%) Bradycardia-Tachycardia 0 (0%) 0 (0%) 0 (0%) Syndrome Other 2(6.9%) 0 (0%) 2 (2.6%) Atrial Arrhythmia History (N, %) None 14 (48.3%)36 (73.5%) 50 (64.1%) Atrial Tachycardia 4 (13.8%) 0 (0%) 4 (5.1%)Paroxysmal 4 (13.8%) 0 (0%) 4 (5.1%) Recurrent 0 (0%) 0 (0%) 0 (0%)Chronic 0 (0%) 0 (0%) 0 (0%) Atrial Flutter 1 (3.4%) 5 (10.2%) 6 (7.7%)Paroxysmal 1 (3.4%) 4 (8.2%) 5 (6.4%) Recurrent 0 (0%) 1 (2%) 1 (1.3%)Chronic 0 (0%) 0 (0%) 0 (0%) Atrial Fibrillation 11 (37.9%) 9 (18.4%) 20(25.6%0 Paroxysmal 8 (27.6%) 3 (6.1%) 11 (14.1%) Recurrent 0 (0%) 4(8.2%) 4 (5.1%) Chronic 3 (10.3%) 1 (2%) 4 (5.1%)

The next table shows patient family history that was included in thespecimen profiles and the relative breakdown between the control andtest groups.

Patients in Patients in Total ICD Arm Control Arm Patients PatientCharacteristics (N = 29) (N = 49) (N = 78) Patient Family History (N, %)None 20 (69%) 31 (63.3%) 51 (65.4%) Long Q/T Syndrome 0 (0%) 0 (0%) 0(0%) Grandparent 0 (0%) 0 (0%) 0 (0%) Parent 0 (0%) 0 (0%) 0 (0%)Sibling 0 (0%) 0 (0%) 0 (0%) Cousin 0 (0%) 0 (0%) 0 (0%) Sudden CardiacDeath 5 (17.2%) 11 (22.4%) 16 (20.5%) Grandparent 0 (0%) 1 (2%) 1 (1.3%)Parent 4 (13.8%) 8 (16.3%) 12 (15.4%) Sibling 1 (3.4%) 3 (6.1%) 4 (5.1%)Cousin 0 (0%) 1 (2%) 1 (1.3%) Sudden Death 3 (10.3%) 4 (8.2%) 7 (9%)Grandparent 0 (0%) 0 (0%) 0 (0%) Parent 3 (10.3%) 3 (6.1%) 6 (7.7%)Sibling 1 (3.4%) 1 (2%) 2 (2.6%) Cousin 0 (0%) 0 (0%) 0 (0%) Syncope 2(6.9%) 1 (2%) 3 (3.8%) Grandparent 0 (0%) 0 (0%) 0 (0%) Parent 2 (6.9%)0 (0%) 2 (2.6%) Sibling 0 (0%) 1 (2%) 1 (1.3%) Cousin 0 (0%) 0 (0%) 0(0%) Deafness 1 (3.4%) 4 (8.2%) 5 (6.4%) Grandparent 0 (0%) 1 (2%) 1(1.3%) Parent 1 (3.4%) 2 (4.1%) 3 (3.8%) Sibling 0 (0%) 1 (2%) 1 (1.3%)Cousin 0 (0%) 0 (0%) 0 (0%) History of Thrombo-embolic Event No 24(82.8%) 44 (89.8%) 68 (87.2%) Yes 59 17.2%) 5 (10.2%) 10 (12.8%) Timesince most recent event (years) Mean 1.8 4.2 3.2 Standard Deviation 1.46.3 4.7 Maximum-Minimum 0.8-3.4 0.2-13.5 0.2-13.5 Type TIA 2 (6.9%) 1(2%) 3 (3.8%) CVA 2 (6.9%) 1 (2%) 3 (3.8%) PE 0 (0%) 1 (2%) 1 (1.3%)Renal 0 (0%) 0 (0%) 0 (0%) Peripheral 0 (0%) 0 (0%) 0 (0%) Other 1(3.4%) 2 (4.1%) 3 (3.8%) Other History History of Hyperthyroidism 0 (0%)2 (4.1%) 2 (2.6%0 Hearing loss 12 (41.4%) 16 (52.7%) 28 (35.9%)

The table below shows patient lifestyle characteristics that wereincluded in the specimen profiles and the relative breakdown between thecontrol and test groups.

Patients in ICD Patients in Total Arm Control Arm Patients PatientCharacteristics (N = 29) (N = 49) (N = 78) Does the Patient Smoke? No 23(79.3%) 42 (85.7%) 65 (83.3%) Yes  6 (20.7%)  7 (14.3%) 13 (16.7%)Number of years Mean 41.6 39.6 40.4 Standard Deviation 11.1 8  9 Maximum-Minimum 30-55 30-50 30-55 Degree of Smoking 1-2 packs a week 1(3.4%) 2 (4.1%) 3 (3.8%) 3-5 packs a week 0 (0%)   1 (2%)   1 (1.3%)5-10 packs a week 2 (6.9%) 3 (6.1%) 5 (6.4%) 10 or more packs a week 1(3.4%) 0 (0%)   1 (1.3%) Use of Alcohol No 17 (58.6%) 24 (49%)   41(52.6%) Yes 12 (41.4%) 25 (51%)   37 (47.4%) Number of years Mean 36.738.2 37.7 Standard Deviation 17   13.9 14.7 Maximum-Minimum 10-59  4-60 4-60 Degree of Drinking 1-2 drinks a week  5 (17.2%)  6 (12.2%) 11(14.1%) 3-5 drinks a week 1 (3.4%)  7 (14.3%)  8 (10.3%) 5-10 drinks aweek  4 (13.8%)  6 (12.2%) 10 (12.8%) 10 or more drinks a week 2 (6.9%) 5 (10.2%) 7 (9%)  

The following table shows patient baseline medications that wereincluded in the specimen profiles and the relative breakdown between thecontrol and test groups.

Patients in Patients in Total ICD Arm Control Arm Patients PatientMedications (N = 29) (N = 49) (N = 78) Any Medications in Prior 6 Months(N, %) No 0 (0%) 0 (0%) 0 (0%) Yes 29 (100%) 49 (100%) 78 (100%) Class I4 (13.8%) 1 (2%) 5 (6.4%) Disopyramide 0 (0%) 0 (0%) 0 (0%) Flecainide 0(0%) 0 (0%) 0 (0%) Mexiletine 1 (3.4%) 0 (0%) 1 (1.3%) Moricizine 0 (0%)0 (0%) 0 (0%) Procainamide 2 (6.9%) 0 (0%) 2 (2.6%) Propafenone 0 (0%) 1(2%) 1 (1.3%) Quinidine 1 (3.4%) 0 (0%) 1 (1.3%) Tocainide 0 (0%) 0 (0%)0 (0%) Other 0 (0%) 0 (0%) 0 (0%) Class II 14 (48.3%) 4 (8.2%) 18(23.1%) Amiodarone 8 (27.6%) 2 (4.1%) 10 (12.8%) Dofetilide 0 (0%) 0(0%) 0 (0%) Sotalol 7 (24.1%) 2 (4.1%) 9 (11.5%) Other 0 (0%) 0 (0%) 0(0%) Beta Blockers 17 (58.6%) 36 (73.5%) 53 (67.9%) Atenolol 1 (3.4%) 9(18.4%) 10 (12.8%) Betaxolol 0 (0%) 0 (0%) 0 (0%) Bisoprolol 0 (0%) 0(0%) 0 (0%) Bucindolol 0 (0%) 0 (0%) 0 (0%) Carvedilol 4 (13.8%) 3(6.1%) 7 (9%) Metoprolol 11 (37.9%) 22 (44.9%) 33 (42.3%) Nadolol 0 (0%)0 (0%) 0 (0%) penbutolol 0 (0%) 0 (0%) 0 (0%) Propanolol 1 (3.4%) 2(4.1%) 3 (3.8%) Timolol 0 (0%) 0 (0%) 0 (0%) Other 0 (0%) 1 (2%) 1(1.3%) Calcium Channel Blockers 4 (13.8%) 10 (20.4%) 14 (17.9%)Amlodipine 2 (6.9%) 4 (8.2%) 6 97.7%) Diltiazem 0 (0%) 3 (6.1%) 3 (3.8%)Ibepridil 0 (0%) 0 (0%) 0 (0%) Felodipine 0 (0%) 0 (0%) 0 (0%)Nifedipine 0 (0%) 3 (6.1%) 3 (3.8%) Nisoldipine 0 (0%) 0 (0%) 0 (0%)Nimodipine 0 (0%) 0 (0%) 0 (0%) Verapamil 1 (3.4%) 0 (0%) 1 (1.3%) Other1 (3.4%) 0 (0%) 1 (1.3%) Digoxin 9 (31%) 3 (6.1%) 12 (15.4%)Anti-Coagulants 28 (96.6%) 46 (93.9%) 74 (94.9%) Warfarin 5 (17.2%) 8(16.3%) 13 (16.7%) Aspirin 25 (86.2%) 40 (81.6%) 65 (83.3%) Other 4(13.8%) 14 (28.6%) 18 (23.1%) Other 26 (89.7%) 39 (79.6%) 65 (83.3%)

Protein analysis from patient blood samples was carried out as describedin the previous example. The CART (Classification and Regression Tree)method was used to identify class identifiers. The iterativepartitioning algorithm used the test versus control groupings as theresponse variables and 2076 predictor variables that included 86demographic variables and 1990 protein/peptide variables. Eligibleprotein/peptide variables were identified as peaks in spectral analysisof at least 4% of patients. Each patient's protein level for a givenvariable was averaged from two peak measurements.

FIG. 8 is the resulting tree analysis from the CART analysis. Treeanalysis 108 uses the five identified class identifiers P5, P6, P7, P8and P9 to classify all patients, represented as group 110, based on riskfor fatal VT/VF.

The most effective class identifier is protein P5. Fifteen patientshaving P5 levels less than 0.0300685765 (measured in arbitrary units)were placed in group 112. Thirteen, or 86.7%, were test patients withIMDs. Sixty-three patients having P5 levels greater than or equal to0.0300685765 were placed in group 114. Sixteen, or 25.4%, were testpatients.

The class identifier shown to further partition group 112 andrepresented as P6 was consumption of alcohol or lack of consumption forless than 20 years. Ten patients (eight of which had never consumedalcohol) were placed in group 116. All ten patients, or 100%, were testpatients. Five patients that had consumed alcohol for more than 20 yearswere placed in group 118. Three of these five patients, or 60%, weretest patients.

Group 114 was then further partitioned based on levels of protein P7.Twenty patients having P7 levels greater than or equal to 0.1759674485were placed into group 120. All twenty, or 100%, were control patients.Forty-three patients having P7 levels less than 0.1759674485 were placedinto group 122. Twenty-seven of these forty-three patients, or 62.8%,were control patients.

Group 122 was further partitioned based on levels of protein P8.Thirteen patients having P8 levels less than 0.314539267 were placedinto group 124. All thirteen, or 100%, were control patients. Thirtypatients having P8 levels greater than or equal to 0.314539267 wereplaced into group 126. Fourteen of these thirty patients, or 46.7%, werecontrol patients.

Further partitioning of group 126 was based on levels of protein P9.Thirteen patients having P9 levels of less than 0.0935425805 were placedinto group 128. Twelve of these patients, or 92.3%, were test patients.Seventeen patients having P9 levels greater than or equal to0.0935425805 were placed into group 130. Only four of these seventeenpatients, or 23.5%, were test patients.

Thus, when applying tree analysis 108, patients falling into groups 116and 128 have a significant risk of experiencing VT/VF and would benefitfrom an IMD. Conversely, patients falling into groups 120, 124, and 130do not have a significant risk of experiencing VT/VF.

The table below summarizes the percentage of test patients belonging toeach group of tree analysis 108.

P5 P6 P7 P8 P9 Col. 6 Col. 7* <0.0300685765 Subtotal 15 86.7 ≧20 years 560  <20 years 10 100 ≧0.0300685765 N/A Subtotal 63 25.4 ≧0.1759674485 200 <0.1759674485 Subtotal 43 37.2 <0.314539267 13 0 ≧0.314539267 Subtotal30 53.3 ≧0.0935425805 17 23.5 <0.0935425805 13 92.3 Total 78 37.2 *Eachpercentage is for the applicable group of the corresponding row;therefore the percentages do not sum to 100%, as they are calculatedwith different denominators (patient sample sizes). Columns one throughfive represent the class identifiers, P5-P9 and rows represent groups112-130 obtained by using the class identifiers. Column 6 (Col. 6) isthe total number of patients belonging to each corresponding group, andcolumn 7 (Col. 7) is the percentage of patients in each group that aretest patients.

For example, to assess the percentage of test patients among allpatients having P5 levels greater than or equal to 0.0300685765 and P7levels less than 0.1759674485, begin at column 1 and select the rowcorresponding to ≧0.0300685765. Move to columns 2 and 3 (column 2 doesnot apply to these specific patients) and select the row in column 3corresponding to <0.1759674485. Moving across to column 6, the number ofpatients having these class identifiers is 43, and the corresponding rowin column 7 indicates that 37.2% of the 43 patients were test patients.

The following table summarizes the information regarding proteins P5,P7, P8, and P9.

Partitioning Molecular Fraction of Spectrum Peak Weight Chip TypeIsolation Range Intensity P5 Immobilized Combined High 0.030068576511991 Metal Affinity fractions f2 Protein Surface and f3 containing pH5-7 P7 Weak Cation Fraction 1 High 0.1759674485 10552.4 Exchangecontaining Protein Surface flow- through and pH = 9 P8 Weak CationFraction 1 High 0.314539267 43529.4 Exchange containing Protein Surfaceflow- through and pH = 9 P9 Hydrophobic Fraction 1 Protein 0.093542580513806.8 Surface containing flow- through and pH = 9

The analysis resulted in four protein class identifiers and onedemographic class identifier that correctly classifies patients based onrisk of experiencing a true VT/VF episode.

The test procedures described above are not unique, nor are theynecessarily the most efficient method of sorting patients who arecandidates for an IMD from those that are not. Nevertheless, theseprocedures are illustrations of tests that can be used to screenpatients to find out the ones who have a propensity for ventriculartachyarrhythmia and thus may be at increased risk of sudden cardiacdeath.

Depending upon the biochemical markers of interest, measurements ofmass, concentration or abundance may be less important thandetermination of whether the marker is present or absent. The inventionencompasses embodiments in which measurement of a biochemical marker ina patient includes determining whether the marker is present or not. Forexample, animal experimentation may establish that animals sufferingsudden cardiac death exhibit an absence of a set of proteins andpeptides having particular molecular weights. Similarly, animalexperimentation may establish that animals suffering sudden cardiacdeath exhibit proteins or peptides that are otherwise not present.Detection of the presence or absence of such proteins or peptides in ahuman sample may have clinical significance, as the presence or absenceproteins or peptides may be indicative of risk of sudden cardiac death.

In some cases, what is of interest is not the presence or absence of abiochemical marker, or its concentration on a single occasion, but anincrease or decrease in the concentration or the rate of change, asdemonstrated by two or more measurements separated by a time intervalsuch as two weeks or one month. The invention supports consideration ofa change as a basis for assessing a risk of ventricular tachyarrhythmia.

Test procedures such as the exemplary procedures described above can beautomated, in whole or in part. FIG. 9 is an example of a system 132that can perform an automated analysis of biochemical markers and canassess a risk of ventricular tachyarrhythmia in a patient as a functionof the analysis. System 132 includes a sample input model 134, whichreceives a sample for analysis, and a measuring system 136. In oneembodiment of the invention, input module 134 may include one or morebiochips like those depicted in FIG. 5, and measuring system 136 maycomprise a SELDI-based mass analyzer. The invention is not limited tosuch components, however.

A processor 138 receives the measurements from measuring system 136 andassesses a risk of ventricular tachyarrhythmia in the patient as afunction by analyzing the measurements. Processor 138 may apply a treeanalysis, such as the analyses depicted in FIGS. 1, 2, 7, and 8 todetermine whether a patient is at risk of ventricular tachyarrhythmia.Processor 138 may further assess a benefit of implanting a medicaldevice in the patient as a function of the measurements, oradministering an antiarrhythmic drug to the patient.

An output module 140 reports the results of the analysis. Output module140 may comprise a display screen, printer, or any other device thatreports the results of the analysis. A benefit of implanting a medicaldevice in the patient as a function of the measurement is assessed.

The invention may offer one or more advantages. Clinical data suggestthat, in a significant number of cases, sudden cardiac death is theresult of VT or VF. Episodes of VT or VF are treatable with an IMD ormedication. The invention presents techniques for identifying thepatients who are at risk of experiencing ventricular tachyarrhythmia. Asa result, there is an improved chance that these patients will receivelife-saving therapy, thereby reducing their risk of sudden cardiacdeath.

For example, recent evidence shows that VT/VF is treatable byadministration of clonidine or vagal nerve stimulation, as well asthrough stimulation by an implantable cardioverter defibrillator (ICD).Thus, biomarkers may be used to identify patients that would benefitfrom these treatments and/or benefit from IMDs such as a drug pump todeliver intrathecal clonidine, a vagal nerve stimulator, or an ICD.

Therapies involving an IMD or medication need not be exclusive of oneanother. Furthermore, the invention supports therapies in addition toimplantation of an IMD or regulation of a regimen of mediation. In somecircumstances, the biomarkers may be more than symptomatic or indicativeof the risk of VT or VF, and may be substantially causally related tothe risk of VT or VF. In such circumstances, therapy may be directed tothe biomarkers.

It may be possible, for example, to treat the patient by adjusting theconcentration of biomarkers. When a concentration of certain proteinbiomarkers is found to be lower in a patient with VT or VF, then perhapsthe patient can be treated by injecting those proteins into the blood,thereby restoring a more healthful concentration of the biomarkers.Conversely, when a concentration of certain protein biomarkers is foundto be higher, then perhaps the patient can be treated by reducing theconcentration of the protein biomarkers. A high concentration can bereduced by, for example, injection of enzymes that cleave or inhibit theactivity of one or more protein biomarkers. Similarly, gene therapy canbe used to alter protein and gene expression levels. Consequently,application of therapy may include determining one or more proteins orone or more genes, or a combination thereof, to be delivered to thepatient.

The techniques of the invention may call for a sample from the patient.In many embodiments, the sample is one that is taken as a matter ofcourse in a medical examination, such as a blood sample.

Further, the invention should reduce the incidents of false positivesand false negatives. As a result, there is a better chance that patientsthat can benefit from an IMD will have a chance to receive an IMD. Inaddition, the invention includes the capability of being self-improving.As more clinical data are collected, different or more detailed treeanalyses or other sorting techniques may be developed. Empiricalexperience may make tests more sensitive and more specific.

Various embodiments of the invention have been described. Variousmodifications can be made to the described embodiments without departingfrom the scope of the invention. For example, the invention is notlimited to consideration of biochemical markers exclusively. Theassessment of risk of ventricular tachyarrhythmia in the patient mayalso be a function of other measurable physiological factors.Electrophysiological measurements, such as an electrocardiogram, andhemodynamic factors, such as a measurement of ejection fraction, may betaken into consideration. Demographic factors such as the number of CABGprocedures as well as alcohol and tobacco use are also factors that maybe included. System 110 in FIG. 9 may further include a sensor tomeasure a physiological factor, and processor 116 may assess a risk ofventricular tachyarrhythmia as a function of the measurement of thephysiological factor.

Although the invention has been described with proteins as biochemicalmarkers, the invention is not limited to proteins. The invention alsosupports consideration of other markers, such as genetic markers, lipidmarkers and lipoprotein markers. The markers may be considered alone orin combination. For example, the invention supports risk assessments asa function of combinations of gene and protein markers. Techniques suchas nuclear magnetic resonance, gene sequencing, or single nucleotidepolymorphism (SNP) may be used to identify these markers. Considerationof markers such as these may result in enhanced sensitivity andspecificity.

Analysis can e done using multiple techniques. In addition to generatinga sorting tree, applying a logical analysis such as an IF-THENstatement, and artificial neural networks, one can assess a risk ofventricular tachyarrhythmia using linear clustering techniques (e.g.,proximity, similarity, dissimilarity, weighted proximity, and principlecomponent analysis) non-linear clustering techniques (e.g., artificialneural networks, Kohonen networks, pattern recognizers and empiricalcurve fitting), as well as logical procedures (e.g., CART, partition andhierarchical clustering algorithms). The invention is not limited tothese techniques, however, and encompasses other linear analysis,non-linear analysis, logical analysis and conditional techniques.

Some of the techniques described above may be embodied as acomputer-readable medium comprising instructions for a programmableprocessor such as processor 138 in FIG. 9. The programmable processormay include one or more individual processors, which may actindependently or in concert. A “computer-readable medium” includes butis not limited to read-only memory, Flash memory and a magnetic oroptical storage medium.

Although the present invention has been described with reference topreferred embodiments, workers skilled in the art will recognize thatchanges may be made in form and detail without departing from the spiritand scope of the invention.

1-16. (canceled)
 17. A method for assessing a risk of ventriculartachyarrhythmia in a patient using a plurality of biochemical markers,comprising: assessing the risk of ventricular tachyarrhythmia as afunction of a measurement M_(A) of a first biochemical marker A in thepatient; and assessing the risk of ventricular tachyarrhythmia as afunction of a measurement M_(B) of a second biochemical marker B in thepatient; wherein M_(A) is compared to a threshold value T_(A) of A, andwherein M_(B) is compared to a threshold value T_(B) of B.
 18. Themethod according to claim 17, wherein the biochemical markers comprisesone of a protein, a lipid, and a gene.
 19. The method according to claim17, wherein assessing the risk of ventricular tachyarrhythmia comprisesone of generating a sorting tree, generating a logical test, generatingan artificial neural network, and assessing the risk of at least one ofventricular tachycardia, ventricular fibrillation, and sudden cardiacdeath.
 20. The method according to claim 17, further comprising:assessing the benefit of administering a drug to the patient.
 21. Themethod according to claim 20, wherein the drug is an anti-arrhythmicdrug.
 22. The method according to claim 17, further comprising:assessing the benefit of implanting a medical device in the patient. 23.The method according to claim 22, wherein the medical device comprisesat least one of an electronic cardiac stimulation device and a drugdelivery device.
 24. The method according to claim 17, wherein themeasurement of a biochemical marker comprises one of a mass measurementof the biochemical marker, a mass-to-charge ratio measurement of thebiochemical marker with a mass spectrometer, and an isoelectric pHmeasurement of the biochemical marker.
 25. The method according to claim17, further comprising: assessing the risk of ventriculartachyarrhythmia in the patient as a function of a measurement of aphysiological factor in the patient.
 26. The method according to claim25, wherein the physiological factor comprises at least one of anelectrophysiological factor and a hemodynamic factor.
 27. The methodaccording to claim 17, further comprising: assessing the risk ofventricular tachyarrhythmia in the patient as a function of a reactionbetween a biological sample from a patient and a plurality of sensingelements of a biochip that is exposed to the biological sample.
 28. Themethod according to claim 27, wherein assessing the risk of ventriculartachyarrhythmia in the patient as a function of a reaction between thesample and the sensing elements comprises performing mass spectrometryon the biochip.
 29. The method according to claim 28, wherein performingthe mass spectroscopy comprises performing a Surface Enhanced LaserDesorption/Ionization process.
 30. The method according to claim 17,wherein the measurement of a biochemical marker comprises the change inconcentration of the biochemical marker over time.
 31. The methodaccording to claim 17, further comprising applying a therapy to thepatient as a function of the assessment of risk.
 32. The methodaccording to claim 31, wherein applying a therapy to the patientcomprises one of implanting an electronic cardiac stimulation device inthe patient, administering an anti-arrhythmic drug to the patient, anddetermining at least one of a protein and a gene to be delivered to thepatient.
 33. The method according to claim 17, further comprising:assessing the risk of ventricular tachyarrhythmia as a function ofM_(A), M_(B), and a measurement M_(C) of a biochemical marker C in thepatient; wherein M_(C) is compared to a threshold value T_(C) of C. 34.The method according to claim 17, further comprising: assessing the riskof ventricular tachyarrhythmia as a function of M_(A), M_(B), and ameasurement M_(D) of a biochemical marker D in the patient; whereinM_(D) is compared to a threshold value T_(D) of D.
 35. The methodaccording to claim 33, further comprising: assessing the risk ofventricular tachyarrhythmia as a function of M_(A), M_(B), M_(C), and ameasurement M_(D) of a biochemical marker D in the patient; whereinM_(D) is compared to a threshold value T_(D) of D.
 36. The methodaccording to claim 34, further comprising: assessing the risk ofventricular tachyarrhythmia as a function of M_(A), M_(B), M_(D), and ameasurement M_(C) of a biochemical marker C in the patient; whereinM_(C) is compared to a threshold value T_(C) of C.